Method of treating surfaces

ABSTRACT

Disclosed herein are methods of treating an article surface. The method comprises removing a metal oxide surface from the metal substrate to expose a metal surface; and delivering particles comprising a dopant from at least one fluid jet to the metal surface to impregnate the surface of the article with the dopant. The method also comprises delivering substantially simultaneously a first set of particles comprising a dopant and a second set of particles comprising an abrasive from at least one fluid jet to a surface of an article to impregnate the surface of the article with the dopant.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/611,433, filed on Feb. 2, 2015, now U.S. Pat. No. 9,242,268, which isa continuation of U.S. application Ser. No. 14/517,548, filed on Oct.17, 2014, now U.S. Pat. No. 9,034,422, which is a continuation of U.S.application Ser. No. 13/308,126, filed on Nov. 30, 2011, now U.S. Pat.No. 8,889,212, which is a divisional of U.S. application Ser. No.11/853,764, filed on Sep. 11, 2007, now U.S. Pat. No. 8,119,183, whichclaims the benefit of priority under 35 U.S.C. §119 to U.S. ProvisionalApplication No. 60/910,464, filed on Apr. 6, 2007, the disclosure ofwhich is incorporated herein by reference, and to Irish Application No.2006/0669, filed on Sep. 11, 2006.

FIELD OF THE INVENTION

The present invention relates to methods of bombarding surfaces ofarticles, such medical devices, with dopants.

BACKGROUND OF THE INVENTION

The bombardment of metal surfaces with so-called abrasive materials isfinding an increasing number of technical applications in recent years.Techniques such as grit blasting, shot blasting, sand blasting, shotpeening and micro abrasion fall under this category of surface treatmenttechnique. In each of these techniques, generally, an abrasive material,shot or grit, is mixed with a fluid and delivered at high velocity toimpinge the surface to be treated. The technique used to deliver theabrasive material can be classified as wet or dry depending on thechoice of fluid medium used to deliver the abrasive to the surface,usually water and air respectively. The generic term “abrasivebombardment” is used to refer to all such techniques in thisspecification.

Applications of these technologies include metal cutting, cold workingmetallic surfaces to induce desirable strain characteristics and thepre-treatment of surfaces to induce desirable texture (surfaceroughness) for the purposes of enhanced adhesion of further coatingmaterials. (See Solomon et al., Welding research, 2003. October: p.278-287; Momber et al., Tribology International, 2002. 35: p. 271-281;Arola et al., J. Biomed. Mat. Res., 2000. 53(5): p. 536-546; and Arolaand Hall, Machining science and technology, 2004. 8(2): p. 171-192). Anexample of the latter is to be found in the biomedical sector wheretitanium implants are grit blasted with alumina or silica to achieve anoptimum level of surface roughness that will maximize the adhesion ofplasma sprayed hydroxyapatite (HA) coatings on the surface of theimplants. HA coated implants are desirable because of the biomimeticproperties of the apatite layer but an optimum bonding strength betweenthe titanium surface and the apatite layer is also necessary.

It has been known for some time that during the bombardment of thesesurfaces some of the abrasive material becomes impregnated in thesurface of the metal itself, which has generated some interest in thesetechniques as possible candidates for modifying surface chemistry ingeneral. (See Arola et al. and Arola and Hall, supra). Again withreference to the biomedical sector one study has looked at shot blastingas a means of putting a hydroxyapatite layer directly on to a titaniumsurface in an effort to bypass the costly plasma spray process.Ishikawa, K., et al., Blast coating method: new method of coatingtitanium surface with Hydroxyapatite at room temperature. J. Biomed.Mat. Res., 1997. 38: p. 129-134. In this study, HA of an unspecifiedparticle size distribution was used as the abrasive. However, given thatthe deposited layer of apatite could be removed with a benign washingregime it seems that a strong bond with the surface of the metal was notachieved.

Choi et al. (KR20030078480) refer to the use of a single calciumphosphate particle as a grit blasting media for the purposes ofembedding the grit in the surface of dental implants but particle inexcess of 190 μm are disclosed.

U.S. Pat. No. 6,502,442 ([6]) refers to the use of sintered HA as theabrasive using water as the fluid medium. Some impregnation of the HAwas achieved in this instance as the HA was thermally processed.

Muller et al. (US2004158330) disclosed blasting particles comprisingcalcium phosphate contained in a glassy matrix. Other disclosures (e.g.,U.S. Pat. Nos. 4,752,457 and 6,210,715) describe methods for themanufacture of calcium phosphate micro-spheres usually comprising apolymer component and complex methods of manufacturing the same, buttheir effectiveness as blasting media was not elucidated.

The Rocatec™ system for the silicization of metallic and other surfacesalso uses individual particles having multiple components. Thistechnology is used extensively in the dental arena. In this instance analumina particle having an outer adherent layer of silica is propelledat a pre-roughened surface and upon impact the local heat generated inthe vicinity of the impact causes the shattered silica outer layer tobecome fused to the surface a process referred to as ceramicization.

Bru-Magniez et al. (U.S. Pat. No. 6,431,958) have disclosed hardabrasive materials with multiple stratified layers for use in blastingabrasive bombardment techniques to modify surfaces. In this instance thepurpose of the process was to embed or otherwise attach the stratifiedlayer around the abrasive particles to the surface being treated. Theouter layer comprises at least one polymer while the core ceramicmaterial of choice is an oxide, carbide, nitride, or carbonitride.

The use of multiple stratified polymeric layers has been proposed. Langeet al. (U.S. Pat. No. 6,468,658) have disclosed a particle composed of acore base material and an outer adherent layer of titanium dioxide forblasting purposes

Further applications of abrasive bombardment for the purposes of surfacemodification are to be found in the biomedical sector such as forexample the use of micro abrasion to clean the oxide slag from thestruts of laser machined coronary stents and the impregnation of thesurfaces of pacemakers and defibrillators with silica to increase theadhesion of further polymer coatings to the device.

A commonality among these examples is the use of a single type of solidparticle in the fluid stream.

The recent significant interest in surface modification technology as itrelates to biomedical devices is fueled by the success of the DrugEluting Stent (DES). Since the introduction of endovascular techniquesin the 1990's revascularisation strategies have changed dramaticallyover the last number of years. However, in-stent restenosis (ISR)remains a problem wherein rupture of the vessel lining at the stent sitecan cause platelet activation, the secretion of inflammation mediatorsand eventually smooth muscle cell (SMC) formation, a process analogousto scar formation around a wound site. Furthermore as the stent alsocontacts the blood it should not induce a foreign body reaction (FBR) inthe tissue or blood cells, i.e., it should be biocompatible. The DESuses surface modification technology to combat these problems whereinthe surface of the stent is used to deliver active agents(anti-restenosis and anti-thrombosis agents) usually in a polymer matrixlocally to the device site where they are most needed. This technologywas pioneered by Cordis with there Cypher stent which received FDAapproval in 2003. Since then a number of other DES have appeared on themarket all aimed at reducing ISR and thrombosis in patients that havepercutaneous coronary intervention (PCI) procedures. All of these activedevices use a polymer matrix to carry the drug on the surface of thestent and control its elution characteristics in vivo.

However problems have arisen with the DES attributed to a number offactors, among them, achieving proper control of the elutioncharacteristics of the drug(s). The polymer matrix (which degrades withtime to release the drug and the polymer degradation products) has beenidentified as a possible culprit in patients with hypersensitivity.Thus, there are continuing efforts to develop new methods to control thedelivery and elution of the drugs.

A large body of prior art in the stent arena has been directed towardsachieving passive coatings on the stent surface to mediate ISR. Theseinclude such processes as nitriding and carbon-nitriding, the use ofcarbon and silicon carbide coatings as well as processes to thicken oraugment the native oxide layer on the surface of the stent materialsincluding oxidation, ion implantation and electrochemical treatmentssuch as electropolishing or electroplating with inert metals. All suchprocesses however have a number of disadvantages and no one treatmenttechnique as such provides the ideal surface for optimal clinicalresults.

Another arena of relevance is the area of biofilm formation at thesurfaces of implantable devices wherein bacteria at the surface ofimplant surfaces arrange themselves into films with three dimensionalmacroscopic structure. In this instance the film itself can represent abarrier to standard antimicrobial treatments such as for example thesystemic use of antibiotics. It is reported that the systemic dose ofantibiotic required to kill bacterial biofilm infections can be up to1000 times the systemic dose required to kill their planktoniccounterparts in suspension often inducing unwanted and serious sideeffects in patients. Localized drug delivery at the surfaces ofimplantable devices has been mentioned as one method to targetantimicrobial agents at the implant surface where they are most needed,preventing biofilm formation with the added advantage of using muchlower dose rates than systemic treatments.

Currently most bactericidal strategies for localized drug delivery usepolymer coatings or polymer micro spheres embedded in other suitablecarrier matrices as carriers for antibacterial agents. In additioncalcium phosphate salts including hydroxyapatite have been proposed assuitable carriers for antibiotics. Biomimetic deposition has been usedto deposit nano crystalline apatite layers on the surfaces of orthopedicmetallic implants that can then be loaded with drugs precipitated ontothe inorganic coating from solution in a separate step (US20040131754).Such strategies can have dual advantage as for example in the arena oforthopedic implants where the calcium phosphate salt provides anosteoconductive benefit at the surface inducing bone in-growth in vivowhile the antibiotic reduces the risk of biofilm formation, both factorscontributing heavily to the need for revision procedures. However thisapproach is limited by the available surface area at the surface of theimplant as this determines the amount of antibiotic that can be loaded.Furthermore the approach is multi-step as often the attachment of theceramic layer involves high temperature (as for example in the case ofplasma sprayed calcium phosphate coatings) or the attachment of the drugrequires precise control of the pH and other process parametersprecluding the simultaneous attachment of the inorganic salt and theantibacterial agent. Among the antibiotics that have been attached tometal surfaces via such methods are gentamycin, tobramycin, vancomycin,ampicillin, and others.

The range of therapeutic agents that could provide benefit for patientsif present at the surface of implants is not limited to antibiotics orimmuno-suppressants. Several studies have focused on placing othertherapeutic agents at the surface of implantable devices to inducedesirable in vivo responses. For example, some studies have focused onplacing the functional molecules involved in these cascades at thesurfaces of the implants. These include for example proteins among themhormones, growth factors, structural proteins, immunogens and antigens.As a corollary of this much work has focused on the design of peptidesand proteins that have structural similarity to the active sites of theproteins involved in biological pathways. For example the use of RGDpeptides in orthopedic applications, or bactericidal peptides have beenproposed as strategies for combating bacterial infection in instances,e.g., where the bacteria have high resistance to conventionalantibiotics.

As medical implants are increasingly tailored to the needs of thepatient they can also be viewed as a means to deliver therapeutic agentsfor the treatment of other more patient specific diseases for examplediabetes, cancers and other diseases not directly related to the primaryfunction of the implant. An in vivo device lends itself to multiplefunctions wherein the surface of the device becomes a vehicle to delivertherapeutic agents that might be required to treat other diseases thepatient may have.

The limiting factors in achieving therapeutic agent delivery capacity atthe surfaces of implants generally surround the engineering andprocessing aspects. Methods to put these agents on the surface arerequired that are commensurate with maintaining the activity andstructural integrity of the agents themselves and controlling thesurface chemistry particularly there elution kinetics in vivo. As manyof the agents desired are biological in nature, temperature and solutionparameters such as pH etc can present barriers to realizing the benefitof the above mentioned surface modification strategies.

Surface modification of implant surfaces is not limited to the field oftherapeutic agent delivery alone. In many cases surface modification ofthe implantable device may be required for the purposes of tailoring thephysical properties of the surface such as, for example, in titaniumbased devices used in coronary intervention procedures, and in thetreatment of pathological calcifications such as kidney stones. Itwould, however, be desirable to have devices with higher radio-opacitythan that currently associated with these devices in vitro. This wouldfacilitate their radiographic or even magnetic resonance imagingexternally and dispense with the need for invasive procedures orendoscopes currently used with minimally invasive procedures. Examplesinclude the doping of nitinol alloys with tertiary heavy elements suchas platinum, palladium or tungsten among others to increase the radioopacity of the resulting alloy for biomedical and other applications(U.S. Pat. Nos. 7,128,757, 6,776,795, and 6,569,194).

SUMMARY OF THE INVENTION

The present invention is directed towards providing an improvedtreatment process for the purposes of modifying the surfaces ofarticles, such as metallic articles with desirable materials so as toinduce at least one of desirable chemical, physical and/or biologicalcharacteristics in those surfaces.

One embodiment provides a method of treating a metal substrate,comprising:

removing a metal oxide from a surface of the metal substrate to expose ametal surface; and

delivering particles comprising a dopant from at least one fluid jet tothe metal surface to impregnate the surface of the substrate with thedopant.

One embodiment provides a method of treating an article surface, themethod comprising:

delivering substantially simultaneously a first set of particlescomprising a dopant and a second set of particles comprising an abrasivefrom at least one fluid jet to a surface of an article to impregnate thesurface of the article with the dopant.

In other embodiments, the dopant can be polymers, metals, ceramics,therapeutic agents, and combinations thereof. The article can be amedical device, such as an implantable medical device.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the invention will be understood from thefollowing description, the appended claims and the accompanyingdrawings, in which:

FIG. 1 is a schematic representation of a treatment process of theinvention;

FIG. 2 shows (a) an XPS spectrum of cp titanium surfaces grit blastedwith HA only; and (b) an XPS spectrum of cp titanium surfaces gritblasted with HA:Alumina mix;

FIGS. 3A and 3B show comparative XPS spectra of Ca 2p (FIG. 3A) and P 2p(FIG. 3B) core levels of HA only blasted cp titanium (fine line) and50:50 HA:alumina blasted cp titanium (coarse line);

FIG. 4 shows XPS spectra of the Ti 2p core level on the sample gritblasted with 100% HA (top) and the sample grit blasted with a 50:50HA:alumina mix (bottom);

FIG. 5 shows XPS maps of a 0.2×0.2 mm square on cp titanium surfacesshowing (a) concentration and distribution of Ca on 50:50 grit blastedsample, (b) concentration and distribution of Ti on 50:50 grit blastedsample; (c) concentration and distribution of Ca on the 100% HA gritblasted sample; (d) concentration and distribution of Ti on the 100% HAgrit blasted sample;

FIGS. 6A and 6B show comparative XPS spectra of the Ca 2p and P 2p corelevels in the case of HA only blasted Cp titanium (fine line) and 50:50HA:silica bead blasted cp titanium (coarse line);

FIG. 7 is a pair of XPS survey scans of two different samples blastedwith a 50:50 HA/silica bead mix, showing the reproducibility of theresults;

FIG. 8 shows bacterial assays of gentamycin/HA treated surfaces for (1)Staphylococcus aureus, (2) Escherichia coli, and (3) Pseudomonasaeruginosa where the left sample for each assay is a negative control,and “IZ” indicates the growth inhibition zone;

FIGS. 9A, 9B, and 9C are schematic diagrams of three different nozzleconfigurations to deliver the dopants and abrasive to a surface;

FIG. 10, shows three photographs of the inhibition zone (IZ) on an agarplate inoculated with S. aureus and exposed to vancomycin coupon (Plate1) and inoculated with E. Coli and exposed to Tobramycin (Plates 2 and3);

FIG. 11A shows FTIR spectra of duplicate 100 μm alumina bead samples (a)and (b);

FIG. 11B shows FTIR spectra of duplicate 150 μm alumina bead samples (a)and (b);

FIG. 12A is an XRD pattern of surface HA (alumina; 50 μm);

FIG. 12B is an XRD pattern of surface HA (alumina; 100 μm);

FIG. 13 show XPS survey spectra for duplicate HA controls;

FIG. 14 is an SEM (scanning electron microscopy) image of an HA adlayeron a stainless steel (ASTM F1586) surface;

FIG. 15 is an energy dispersive x-ray (EDX) spectrum for HA on astainless steel (ASTM F1586) surface;

FIG. 16 is SEM image of HA adlayer on the surface of CP titanium (ASTMF67);

FIG. 17 is EDX spectrum for HA on CP titanium (ASTM F67) surface;

FIG. 18A is an AFM (Atomic Force Microscopy) image of the thickness ofthe HA adlayer on the CP titanium surface;

FIG. 18B is an AFM plot corresponding to the AFM image of FIG. 18A;

FIG. 19 is an SEM image of SiO₂ nanoporous micro-particles on thesurface of Grade 5 Titanium (Ti6AL-4V to ASTM F136);

FIGS. 20A and 20B are SEM images of nanoporous HA adlayer on the surfaceof aluminium at a magnification of ×50 (20A) and ×650 (20B); and

FIG. 21 an SEM image of nanoporous HA adlayer on the surface of nitinol.

DETAILED DESCRIPTION

One embodiment provides a treatment process of impregnating a surface,such as a metal surface, with a dopant. The strength of the bond betweenthe dopant and the surface and the concentration of dopant achieved inor on the surface can be improved over conventional methods of surfaceimpregnation techniques. The invention relates to dopants that inducedesirable chemical, physical and biological properties in the surface ofbiomedical implants.

Generally the dopant is a material that is incorporated in the bombardedsurface but does not extensively impregnate the surface if used as thesole solid component in such a bombardment technique. If the material isdelivered to the surface within a high velocity fluid jet on its own, noor minimal surface impregnation will occur. Such circumstances can arisefor a number of reasons; the material may not have sufficient particlesize or be of sufficient density and hardness to breech the metalsurface and impregnate. It may also be a consequence of the nature ofthe surface itself.

In most metallic materials an oxide layer forms at the surface, whichwill be harder than the bulk metal or alloy. Metal surfaces (especiallythose of titanium and titanium derived alloy) are naturally contaminatedin air by a variety of contaminants. The detailed physical and chemicalproperties of any metal surface depend on the conditions under whichthey are formed. The inherent reactivity of the metal can also attractvarious environmental chemicals/contaminants that oxidize on thesurface. For example, titanium is a highly reactive metal, which isreadily oxidized by several different media. This results in titaniumalways being covered in an oxide layer. This oxide layer is chemicallystable but not always chemically inert, as the oxide layer can continueto react with various reactants in its environment, e.g., organicmolecules. Traditionally, modification of the titanium surface/oxidelayer whereby any new materials in the oxide layer occurred as aby-product of that process. In some cases the new material in the oxidelayer can be advantageous to the eventual functionality of the surfacesaffected; however, in some cases the new material can constitute anunwanted intrusion. (“Titanium in Medicine,” D. M. Brunette; P.Tengvall; M. Textor; P. Thompson, Springer, New York; ISBN3-540-66936-1.)

The present invention is directed to the intentional addition of amaterial of choice to the surface. One embodiment takes advantage of theinherent reactivity of metals by the temporary removal of the oxidelayer overlying the metal substrate, and treating the newly exposedmetal beneath to add a new material (a dopant). Depending on the natureof that added material, the surface properties of the metal article canbe tailored according to its intended functional requirements.

Titanium and its alloys always form an oxide layer at the surface. Thisoxide layer is typically inert and unreactive, while titanium itself ishighly reactive and will instantaneously form an oxide layer on exposureto atmospheric environment. Formation of an oxide layer is often adesired property of an implant device.

Examples of dopants in the biomedical device sector includes e.g.,hydroxyapatite, drug eluting polymers and other drug delivery systems,and the article to be impregnated comprises a metal such as, e.g.,titanium, steel, cobalt chrome and alloys thereof.

Accordingly, one embodiment of the present invention provides a methodof treating a metal substrate, comprising:

removing a metal oxide from a surface of the metal substrate to expose ametal surface; and

delivering particles comprising a dopant from at least one fluid jet tothe metal surface to impregnate the surface of the substrate with thedopant.

In one embodiment, the metal surface is sufficiently reactive in thepresence of air that a new oxide layer can form, thus preventingaddition of dopant to a metal surface layer. In one embodiment, thepresent invention involves adding the dopant prior to reoxidation of thenewly formed metal surface. In one embodiment, the step of removing themetal oxide surface is performed under an inert atmosphere. In anotherembodiment, the removing is performed substantially simultaneously withthe delivering such that the metal surface is not substantially oxidizedprior to the delivering.

The metal oxide layer can be removed by a variety of techniques. In oneembodiment, the removing comprises abrasively blasting the metal oxidesurface. the step of abrasively blasting in itself can be performed by anumber of methods, e.g., grit blasting, micro blasting, water jetblasting, and shot peening, as discussed in further detail below, aswell as any other means of abrasive bombardment as known in the art. Inone embodiment, the step of abrasively blasting is performedsubstantially simultaneously with the step of delivering the particlescomprising the dopant, e.g., two streams of particles can be aimed atthe metal oxide surface where one stream abrasively blasts the oxidesurface to expose the new metal surface and the other stream bombardsthe new metal surface with dopant.

In another embodiment, the removing is selected from at least one stepof drilling, cutting, forming, milling, micromachining, scratching,grinding, polishing, and abrading. In another embodiment, the removingis selected from at least one step of acid etching, alkaline etching,and treating with hydrogen peroxide. In yet another embodiment, theremoving comprises a laser treatment selected from ablation,marking/etching, welding, cutting, and cladding. In another embodiment,the removing comprises a plasma treatment selected from etching andcleaning.

As stated above, in certain of the embodiments described herein, theprocess of the oxide removal may be performed in an inert environment toexpose the new metal surface for a sufficient time to conduct thetreatment process e.g., the addition of a new material to the surfacebefore re-exposing the surface to an oxygen rich environment. At thattime, the oxide layer can regenerate, but influenced/modified by theentrapped added dopant(s).

In one embodiment, equipment for removing the oxide layer prior to orsubstantially simultaneously with bombarding the surface can beincorporated with the fluid jet as a stand alone unit or can beincorporated into a manufacturing line. The equipment can be used in apoint of use setting whereby it would constitute an aseptic surgerybased machine that a surgeon could use in an operating room forcustom/prescriptive surface modification prior to implantation of thedevice in the patient. Disposable dopant carrier/filter cartridges canbe used to avoid therapeutic cross contamination and ease of cleaning.

If the dopant is delivered simultaneously to the surface with anabrasive impacting with sufficient energy (a material with sufficientparticle size, density and hardness) to breech the oxide layer a windowof opportunity can be created where the dopant material may be taken upby the surface before the oxide layer reforms around it. The dopantmaterial can become strongly bound within the oxide layer of thesurface. Thus, the surface can be impregnated with materials that impartdesirable properties to the surface in a cost effective manner atordinary temperatures. Furthermore the energy dissipated at the impactsite of the abrasive may be sufficient for the dopant to becomeceramicised or otherwise bonded to the surface. Accordingly, oneembodiment provides a method of treating an article surface, the methodcomprising delivering substantially simultaneously a first set ofparticles comprising a dopant and a second set of particles comprisingan abrasive from at least one fluid jet to a surface of an article toimpregnate the surface of the article with the dopant.

One embodiment of the present invention relates to the impregnation ofmetallic surfaces with a material of choice (here after dopant) usingconventional abrasive bombardment techniques by mixing the dopants withan abrasive (shot or grit) material of choice at the surface. Theabrasive, impinging the surface with sufficient force to breech theoxide layer or otherwise deform the surface to be treated, creates awindow of opportunity wherein the dopant(s) may be taken up by thesurface or otherwise incorporated into or onto the surface.

The embodiments of the invention are encompassed in but not limited tothe schematic representation of the invention in FIG. 1. FIG. 1 (left)schematically shows a fluid jet (nozzle) 2 that simultaneously deliversa stream 3 comprising a set of abrasive particles 4 and a set of dopantparticles 6. Particle sets 4 and 6 bombard a surface 10 of a substrate8. In one embodiment, the substrate 8 is a metal substrate and thesurface 10 is an oxide layer. As a result of bombardment by the abrasiveparticles 4, the surface oxide layer is disrupted, and breaches in theoxide layer 10 result to expose a new surface 10 a of substrate 8(center). In the case of a metal substrate, the newly exposed surface isa metal surface. As the particle stream 3 continues to impinge substrate8, the dopant particles 6 (right) are integrated into the surface 10 ofsubstrate 8. Where the substrate is a metal substrate, a new oxide layer10 reforms around the dopant particles 6.

In certain embodiments, the dopant materials include but are not limitedto materials desired at an implant surface for the purposes of steeringand improving the body tissue-implant interaction. The dopant cancomprise materials such as polymers, metals, ceramics (e.g., metaloxides, metal nitrides), and combinations thereof, e.g., blends of twoor more thereof.

Exemplary dopants include, modified calcium phosphates, includingCa₅(PO₄)₃OH, CaHPO₄.2H₂O, CaHPO₄, Ca₈H₂(PO₄)₆.5H₂O, α-Ca₃(PO₄)₂,β-Ca₃(PO₄)₂ or any modified calcium phosphate containing carbonate,chloride, fluoride, silicate or aluminate anions, protons, potassium,sodium, magnesium, barium or strontium cations.

Other exemplary dopants include titania (TiO₂), zirconia,hydroxyapatite, silica, carbon, and chitosan/chitin.

In one embodiment, the dopant is a combination of an agent-carryingmedia and at least one therapeutic agent (including biomolecules andbiologics). Potential carriers for therapeutic agents includingantibiotics, immuno suppressants, antigenic peptides, bactericidalpeptides, structural and functional proteins have been disclosed in U.S.Pat. No. 6,702,850). Calcium phosphate coatings as the drug carrier canalso be used (see U.S. Pat. Nos. 6,426,114, 6,730,324, and U.S.Provisional Application No. 60/410,307, the disclosures of which areincorporated herein by reference). Dopants that can act asagent-carrying media include nanoporous, mesoporpous, nanotubes,micro-particles of various materials including hydroxyapatite, silica,carbon, and titania (TiO₂) capable of carrying therapeutic agents,biomolecules and biologics. Particulates and powders (e.g. titaniapowder) can be either adhesively bonded or covalently attached(tethered) to the therapeutic agents, biomolecules and biologics.

Composites of media and carriers (e.g. sintered together), andcombinations of carriers can convey drugs and biologics and can controlelution profiles.

Other exemplary dopants include barium titanate, zeolites(aluminosilicates), including siliceacous zeolite and zeolitescontaining at least one component selected from phosphorous, silica,alumina, zirconia, calcium carbonate, biocompatible glass, calciumphosphate glass. The dopant can also be a growth factor consisting ofepidermal growth factors, transforming growth factor α, transforminggrowth factor β, vaccinia growth factors, fibroblast growth factors,insulin-like growth factors, platelet derived growth factors, cartilagederived growth factors, interleukin-2, nerve cell growth factors,hemopoietic cell growth factors, lymphocyte growth factors, bonemorphogenic proteins, osteogenic factors or chondrogenic factors.

In one embodiment, the dopant is hydroxyapatite deposited on a titaniumsurface. Both HA and TiO₂ constitute excellent biocompatiblebiointerfaces, both being biostable and safe in the body. Both can betermed bioreactive in that they can induce specific responses in certaintissues particularly bone tissue. The surface resulting from thedeposition of HA on titanium as delivered by the micro-blastingtechnique combines the benefits of both materials. The TiO₂ is not fullycovered by the dopant (HA) and therefore still presents to thebiological tissue, while the HA affixed on and in the surface is notdenatured by the deposition process and therefore conveys its fullbenefit to the surrounding tissue. In this manner the different benefitsof both biomaterials can brought to bear in the biointerface and whenfurther combined with the surface texture/morphology best suited tointended functionality of the implant, and moreover the availability ofa drug delivery mechanism, can provide various methods for tailoring thetherapeutic, compositional and morphological profile available to thepatient end user.

In one embodiment, the dopant is a therapeutic agent. The therapeuticagent can be delivered as a particle itself, or immobilized on a carriermaterial. Exemplary carrier materials include any of the other dopantslisted herein (those dopants that are not a therapeutic agent) such aspolymers, calcium phosphate, titanium dioxide, silica, biopolymers,biocompatible glasses, zeolite, demineralized bone, de-proteinated bone,allograft bone, and composite combinations thereof.

Exemplary classes of therapeutic agents include anti-cancer drugs,anti-inflammatory drugs, immunosuppressants, an antibiotic, heparin, afunctional protein, a regulatory protein, structural proteins,oligo-peptides, antigenic peptides, nucleic acids, immunogens, andcombinations thereof.

In one embodiment, the therapeutic agent is chosen from antithrombotics,anticoagulants, antiplatelet agents, thrombolytics, antiproliferatives,anti-inflammatories, antimitotic, antimicrobial, agents that inhibitrestenosis, smooth muscle cell inhibitors, antibiotics, fibrinolytic,immunosuppressive, and anti-antigenic agents.

Exemplary anticancer drugs include acivicin, aclarubicin, acodazole,acronycine, adozelesin, alanosine, aldesleukin, allopurinol sodium,altretamine, aminoglutethimide, amonafide, ampligen, amsacrine,androgens, anguidine, aphidicolin glycinate, asaley, asparaginase,5-azacitidine, azathioprine, Bacillus calmette-guerin (BCG), Baker'sAntifol (soluble), beta-2′-deoxythioguanosine, bisantrene HCl, bleomycinsulfate, busulfan, buthionine sulfoximine, BWA 773U82, BW 502U83.HCl, BW7U85 mesylate, ceracemide, carbetimer, carboplatin, carmustine,chlorambucil, chloroquinoxaline-sulfonamide, chlorozotocin, chromomycinA3, cisplatin, cladribine, corticosteroids, Corynebacterium parvum,CPT-11, crisnatol, cyclocytidine, cyclophosphamide, cytarabine,cytembena, dabis maleate, dacarbazine, dactinomycin, daunorubicin HCl,deazauridine, dexrazoxane, dianhydrogalactitol, diaziquone,dibromodulcitol, didemnin B, diethyldithiocarbamate, diglycoaldehyde,dihydro-5-azacytidine, doxorubicin, echinomycin, edatrexate, edelfosine,eflornithine, Elliott's solution, elsamitrucin, epirubicin, esorubicin,estramustine phosphate, estrogens, etanidazole, ethiofos, etoposide,fadrazole, fazarabine, fenretinide, filgrastim, finasteride, flavoneacetic acid, floxuridine, fludarabine phosphate, 5-fluorouracil,Fluosol®, flutamide, gallium nitrate, gemcitabine, goserelin acetate,hepsulfam, hexamethylene bisacetamide, homoharringtonine, hydrazinesulfate, 4-hydroxyandrostenedione, hydrozyurea, idarubicin HCl,ifosfamide, interferon alfa, interferon beta, interferon gamma,interleukin-1 alpha and beta, interleukin-3, interleukin-4,interleukin-6, 4-ipomeanol, iproplatin, isotretinoin, leucovorincalcium, leuprolide acetate, levamisole, liposomal daunorubicin,liposome encapsulated doxorubicin, lomustine, lonidamine, maytansine,mechlorethamine hydrochloride, melphalan, menogaril, merbarone,6-mercaptopurine, mesna, methanol extraction residue of Bacilluscalmette-guerin, methotrexate, N-methylformamide, mifepristone,mitoguazone, mitomycin-C, mitotane, mitoxantrone hydrochloride,monocyte/macrophage colony-stimulating factor, nabilone, nafoxidine,neocarzinostatin, octreotide acetate, ormaplatin, oxaliplatin,paclitaxel, pala, pentostatin, piperazinedione, pipobroman, pirarubicin,piritrexim, piroxantrone hydrochloride, PIXY-321, plicamycin, porfimersodium, prednimustine, procarbazine, progestins, pyrazofurin, razoxane,sargramostim, semustine, spirogermanium, spiromustine, streptonigrin,streptozocin, sulofenur, suramin sodium, tamoxifen, taxotere, tegafur,teniposide, terephthalamidine, teroxirone, thioguanine, thiotepa,thymidine injection, tiazofurin, topotecan, toremifene, tretinoin,trifluoperazine hydrochloride, trifluridine, trimetrexate, tumornecrosis factor, uracil mustard, vinblastine sulfate, vincristinesulfate, vindesine, vinorelbine, vinzolidine, Yoshi 864, zorubicin, andmixtures thereof.

Exemplary therapeutic agents include immunogens such as a viral antigen,a bacterial antigen, a fungal antigen, a parasitic antigen, tumorantigens, a peptide fragment of a tumor antigen, meta static specificantigens, a passive or active vaccine, a synthetic vaccine or a subunitvaccine.

The dopant may be a protein such as an enzyme, antigen, growth factor,hormone, cytokine or cell surface protein.

The dopant may be a pharmaceutical compound such as an anti-neoplasticagent, an anti-bacterial agent, an anti parasitic agent, an anti-fungalagent, an analgesic agent, an anti-inflammatory agent, achemotherapeutic agent, an antibiotic or combinations thereof.

The dopant could also be growth factors, hormones, immunogens, proteinsor pharmaceutical compounds that are part of a drug delivery system suchas those immobilized on zeolite or polymeric matrices, biocompatibleglass or natural porous apitic templates such as coralline HA,demineralised bone, deproteinated bone, allograft bone, collagen orchitin.

In one embodiment, the dopant is an anti-inflammatory drugs selectedfrom non-steroidal anti-inflammatory drugs, COX-2 inhibitors,glucocorticoids, and mixtures thereof. Exemplary non-steroidalanti-inflammatory drugs include aspirin, diclofenac, indomethacin,sulindac, ketoprofen, flurbiprofen, ibuprofen, naproxen, piroxicam,tenoxicam, tolmetin, ketorolac, oxaprosin, mefenamic acid, fenoprofen,nambumetone, acetaminophen, and mixtures thereof. Exemplary COX-2inhibitors include nimesulide, NS-398, flosulid, L-745337, celecoxib,rofecoxib, SC-57666, DuP-697, parecoxib sodium, JTE-522, valdecoxib,SC-58125, etoricoxib, RS-57067, L-748780, L-761066, APHS, etodolac,meloxicam, S-2474, and mixtures thereof. Exemplary glucocorticoids areinclude hydrocortisone, cortisone, prednisone, prednisolone,methylprednisolone, meprednisone, triamcinolone, paramethasone,fluprednisolone, betamethasone, dexamethasone, fludrocortisone,desoxycorticosterone, and mixtures thereof.

Other exemplary therapeutic agents include cell cycle inhibitors ingeneral, apoptosis-inducing agents, antiproliferative/antimitotic agentsincluding natural products such as vinca alkaloids (e.g., vinblastine,vincristine, and vinorelbine), paclitaxel, colchicine,epidipodophyllotoxins (e.g., etoposide, teniposide), enzymes (e.g.,L-asparaginase, which systemically metabolizes L-asparagine and deprivescells that do not have the capacity to synthesize their own asparagine);antiplatelet agents such as G(GP) II_(b)/III_(a) inhibitors, GP-IIainhibitors and vitronectin receptor antagonists;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nitrosoureas (carmustine (BCNU)and analogs, streptozocin), triazenes-dacarbazine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate), pyrimidine analogs (fluorouracil, floxuridine, andcytarabine), purine analogs and related inhibitors (mercaptopurine,thioguanine, pentostatin and 2-chlorodeoxyadenosine (cladribine));platinum coordination complexes (cisplatin, carboplatin), procarbazine,hydroxyurea, mitotane, am inoglutethimide; hormones (e.g., estrogen);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory; antisecretory (breveldin);anti-inflammatory: such as adrenocortical steroids (cortisol, cortisone,fluorocortisone, prednisone, prednisolone, 6α-methylprednisolone,triamcinolone, betamethasone, and dexamethasone), non-steroidal agents(salicylic acid derivatives e.g., aspirin; para-aminophenol derivativese.g., acetominophen; indole and indene acetic acids (indomethacin,sulindac, and etodalac), heteroaryl acetic acids (tolmetin, diclofenac,and ketorolac), arylpropionic acids (ibuprofen and derivatives),anthranilic acids (mefenamic acid, and meclofenamic acid), enolic acids(piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone),nabumetone, gold compounds (auranofin, aurothioglucose, gold sodiumthiomalate); immunosuppressives: (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil); antigenicagents: vascular endothelial growth factor (VEGF), fibroblast growthfactor (FGF); angiotensin receptor blockers; nitric oxide donors;anti-sense oligionucleotides and combinations thereof; cell cycleinhibitors, mTOR inhibitors, and growth factor receptor signaltransduction kinase inhibitors; retinoid; cyclin/CDK inhibitors; HMGco-enzyme reductase inhibitors (statins); and protease inhibitors(matrix protease inhibitors).

In one embodiment, the dopant is an antibiotic chosen from tobramycin,vancomycin, gentamicin, ampicillin, penicillin, cephalosporin C,cephalexin, cefaclor, cefamandole and ciprofloxacin, dactinomycin,actinomycin D, daunorubicin, doxorubicin, idarubicin, penicillins,cephalosporins, and quinolones, anthracyclines, mitoxantrone,bleomycins, plicamycin (mithramycin), mitomycin, and mixtures thereof.

In one embodiment, the dopant is a protein chosen from albumin, casein,gelatin, lysosime, fibronectin, fibrin, chitosan, polylysine,polyalanine, polycysteine, Bone Morphogenetic Protein (BMP), EpidermalGrowth Factor (EGF), Fibroblast Growth Factor (bFGF), Nerve GrowthFactor (NGF), Bone Derived Growth Factor (BDGF), Transforming GrowthFactor-.beta.1 (TGF-.beta.1), Transforming Growth Factor-.beta.(TGF-.beta.), the tri-peptide arginine-glycine-aspartic acid (RGD),vitamin D3, dexamethasone, and human Growth Hormone (hGH), epidermalgrowth factors, transforming growth factor α, transforming growth factorβ, vaccinia growth factors, fibroblast growth factors, insulin-likegrowth factors, platelet derived growth factors, cartilage derivedgrowth factors, interleukin-2, nerve cell growth factors, hemopoieticcell growth factors, lymphocyte growth factors, bone morphogenicproteins, osteogenic factors, chondrogenic factors, or and mixturesthereof.

In one embodiment, the dopant is a heparin selected from recombinantheparin, heparin derivatives, and heparin analogues or combinationsthereof.

In one embodiment, the dopant is an oligo-peptide, such as abactericidal oligo-peptide.

In one embodiment, the dopant is an osteoconductive or osteointegrativeagent.

In one embodiment, the dopant is an immunosuppressant, such ascyclosporine, rapamycin and tacrolimus (FK-506), ZoMaxx, everolimus,etoposide, mitoxantrone, azathioprine, basiliximab, daclizumab,leflunomide, lymphocyte immune globulin, methotrexate, muromonab-CD3,mycophenolate, and thalidomide.

In one embodiment, the carrier material is a polymer such aspolyurethanes, polyethylene terephthalate, PLLA-poly-glycolic acid (PGA)copolymer (PLGA), polycaprolactone,poly-(hydroxybutyrate/hydroxyvalerate) copolymer,poly(vinylpyrrolidone), polytetrafluoroethylene,poly(2-hydroxyethylmethacrylate), poly(etherurethane urea), silicones,acrylics, epoxides, polyesters, urethanes, parlenes, polyphosphazenepolymers, fluoropolymers, polyamides, polyolefins, and blends andcopolymers thereof.

In one embodiment, the dopant is a radio opaque material, such as thosechosen from alkalis earth metals, transition metals, rare earth metals,and oxides, sulphates, phosphates, polymers and combinations thereof.

In one embodiment, the carrier material is a biopolymer selected frompolysaccharides, gelatin, collagen, alginate, hyaluronic acid, alginicacid, carrageenan, chondroitin, pectin, chitosan, and derivatives,blends and copolymers thereof.

In one embodiment, the dopant is delivered in a gaseous carrier fluid,such as nitrogen, hydrogen, argon, helium, air, ethylene oxide, andcombinations thereof. In another embodiment, the dopant is delivered ina liquid carrier fluid. In one embodiment, the liquid is also an etchingliquid (basic or acidic). In one embodiment, the dopant is delivered inan inert environment.

Another embodiment relates to the chemical treatment of metal surfacesfor the purposes of adhesion. Good adhesion of paints and polymericcoatings to metal surfaces is an area of increasing technicalimportance. This technology can be used to pre-treat a surface byimpregnating it with compounds having desired chemical functionality.These include but are not limited to polymers or silica materials havingsiloxane groups.

The pretreatment can be used to lay down a very strongly bound layer ofseed polymer material on the surface. Further polymer coatings couldthen be attached to this seed layer rather than trying to attaching itdirectly to the surface of the metal.

The dopant is not limited to one compound but could be any combinationof any of the materials listed or even any material(s) that do(es) nothave the necessary mechanical properties to impregnate the surface ifdelivered singularly at high velocity to the surface.

In one embodiment, the dopant can be any material so long as it ispassive, i.e., unreactive with the surface. It simply has to be at thesurface when the oxide layer is breeched by the abrasive so that theoxide reforms around it.

In one embodiment, the dopant is nanocrystalline.

In one embodiment, the dopant is nanocrystalline hydroxyapatite.

In one embodiment the abrasive has a suitable property chosen from atleast one of size, shape, hardness, and density to break the oxidelayer. In one embodiment, the abrasive has a Mohs hardness ranging from0.1 to 10, such as a Mohs hardness ranging from 1 to 10, or a Mohshardness ranging from 5 to 10. In another embodiment, the abrasive has aparticle size ranging from 0.1 μm to 10000 μm, such as a particle sizeranging from 1 μm to 5000 μm, or a particle size ranging from 10 μm to1000 μm.

Abrasive materials to be used in this invention include but are notlimited to shot or grit made from silica, alumina, zirconia, bariumtitanate, calcium titanate, sodium titanate, titanium oxide, glass,biocompatible glass, diamond, silicon carbide, calcium phosphate,calcium carbonate, metallic powders, carbon fiber composites, polymericcomposites, titanium, stainless steel, hardened steel, carbon steelchromium alloys or any combination thereof. A broad classification canbe made on the basis of the abrasive material used: shot is generallyconsidered to be hard spherical particles with a well-defined geometryand narrow size range (usually steel, glass or polymeric composites withceramic or fiber mixed through them), grit on the other hand isgenerally a broader term for solid particles or agglomerates that may ormay not be sintered and may or may not be crystalline. Grit willgenerally have a more irregular shape with a broader size distribution.

The pressure of the fluid jet will also be a factor in determining theimpact energy of the abrasive. The abrasive and dopant(s) do not have tobe delivered to the surface through the same jet. They could be in anynumber of separate jets as long as they deliver the solid components tothe surface at the substantially the same time, e.g., prior toreformation of the oxide layer if the surface is a metal. This allows alarge amount of flexibility in optimizing the invention towards aspecific need. In one embodiment, the fluid jet is selected from wetblasters, abrasive water jet peening machines, and wet shot peeningmachines. In one embodiment, the at least one fluid jet operates at apressure ranging from 0.5 to 100 bar, such as a pressure ranging from 1to 30 bar, or a pressure ranging from 1 to 10 bar.

In another embodiment, the at least one fluid jet is selected from dryshot peening machines, dry blasters, wheel abraders, grit blasters),sand blasters(s), and micro-blasters. In one embodiment, the at leastone fluid jet operates at a pressure ranging from 0.5 to 100 bar, suchas a pressure ranging from 1 to 30 bar, or a pressure ranging from 3 to10 bar.

In other embodiments, blasting equipment can be used in conjunction withcontrolled motion such as CNC or robotic control. The blasting can beperformed in an inert environment.

In one embodiment, the dopants and abrasives are contained in the samereservoir and are delivered to a surface from the same jet (nozzle). Inanother embodiment, the dopant is contained in one reservoir andabrasive contained in a separate reservoir, and multiple nozzles deliverthe dopants and abrasives. The multiple nozzles can take the form of ajet within a jet, i.e., the particles from each jet bombard the surfaceat the same incident angle. In another embodiment, the multiple arespatially separated so as to bombard the surface at different incidentangles yet hit the same spot on the surface simultaneously.

FIGS. 9A, 9B, and 9C are schematic diagrams of three different nozzleconfigurations to deliver the dopants and abrasive to a surface: singlenozzle (9A); multiple nozzles with dopants and abrasives delivered fromseparate reservoirs where one nozzle is situated within another nozzle(9B); and multiple, separate nozzles with dopants and abrasivesdelivered from separate reservoirs (9C). More specifically, FIG. 9Ashows a single nozzle 20 for delivering a single stream 23 of abrasiveparticles 24 and dopant particles 26 to a substrate 28. FIG. 9B showsthat multiple nozzles with dopants and abrasives delivered from separatereservoirs can be used, where FIG. 9B illustrates one nozzle 30 fordelivering a stream 33 of abrasive particles 24 situated within anothernozzle 40 for delivering a stream 43 of dopant particles 26, wherestreams 33 and 43 are coaxial. Multiple, separate nozzles with dopantsand abrasives delivered from separate reservoirs can also be used, asindicated in FIG. 9C, which shows nozzles 30 and 40, for deliveringstreams 33 and 43 of abrasive particles 24 and dopant particles 26,respectively.

It can be readily appreciated that where more than one type of dopant isused, dopants can be delivered from a single nozzle, or from separatenozzles. For example, where the dopant combination is a therapeuticagent combined with another particle (e.g., hydroxyapatite), a twonozzle design can be used for delivering the dopant combination from onenozzle and the abrasive from the second nozzle. In another embodiment, athree nozzle configuration can be used where the therapeutic agent isdelivered from a first nozzle, the second set of dopant particles isdelivered from a second nozzle, and the abrasive is delivered from athird nozzle.

In one embodiment, the article is an implantable medical device.Exemplary medical devices include catheters, guide wires, and basketsused in the removal of pathological calcifications. In the case ofbiomedical devices it is desirable that the level of impregnation of theabrasive itself in the surface is minimal. The abrasive should furtherbe biocompatible as it is likely that some impregnation will occur.

In one embodiment, the article is a metal, such as those metals chosenfrom pure metals, metal alloys, intermetals comprising single ormultiple phases, intermetals comprising amorphous phases, intermetalscomprising single crystal phases, and intermetals comprisingpolycrystalline phases. Exemplary metals include titanium, titaniumalloys (e.g., NiTi or nitinol), ferrous alloys, stainless steel andstainless steel alloys, carbon steel, carbon steel alloys, aluminum,aluminum alloys, nickel, nickel alloys, nickel titanium alloys,tantalum, tantalum alloys, niobium, niobium alloys, chromium, chromiumalloys, cobalt, cobalt alloys, precious metals, and precious metalalloys. In one embodiment, the metal is titanium.

In one embodiment the abrasive material is alumina (10 Mesh) while thedopant is HA with a particle size range of 0.1 to 3 μm. The mixed mediais achieved by mixing the dopant and abrasive between the ratio of 5:95and 95:5 HA to Silica volume % but more preferably between the ratio of80:20 to 20:80 and most preferably in the ratio range 60:40 to 40:60.The silica bead has a Mohs hardness in the range of 0.1 to 10 but mostpreferably in the range of 2 to 10 and most preferably in the range 5 to10. This mixed media is delivered to a titanium surface using a standardgrit blasting machine operating in the pressure range of 0.5 Bar to 20Bar, such as a pressure range of 2 to 10 bar, or a pressure range of 4Bar to 6 Bar. The distance between the nozzle and the surface can be inthe range of 0.1 mm to 100 mm, such as a range of 0.1 mm to 50 mm, or arange of 0.1 mm to 20 mm. The angle of the nozzle to the surface canrange from 10 degrees to 90 degrees, such as a range of 30 degrees to 90degrees, or a range of 70 to 90 degrees.

In another embodiment the abrasive material is silica (10 Mesh) whilethe dopant is HA with a particle size range of 0.1 to 3 μm. The mixedmedia is achieved by mixing the dopant and abrasive between the ratio of5:95 and 95:5 HA to alumina weight % but more preferably between theratio of 80:20 to 20:80 and most preferably in the ratio range 60:40 to40:60. The Alumina grit has a Mohs hardness in the range of 0.1 to 10,such as a range of 2 to 10, or a range of 5 to 10. This mixed media canbe delivered to a titanium surface using a standard grit blastingmachine operating in the pressure range 0.5 Bar to 20 Bar, such as apressure range of 2 to 10 bar, a range of 4 Bar to 6 Bar. The distancebetween the nozzle and the surface can range from 0.1 mm to 100 mm, suchas a range of 0.1 mm to 50 mm, or a range of 0.1 mm to 20 mm. The angleof the nozzle to the surface can range from 10 degrees to 90 degrees,such as a range of 30 degrees to 90 degrees, or a range of 70 to 90degrees.

One of ordinary skill in the art can appreciate the influence of machineparameters including jet velocity, operating pressure, venturiconfiguration, angle of incidence and surface to nozzle distances on theextent of impregnation of the dopant in the surface using these mixedmedia.

One of ordinary skill in the art can appreciate the effect of the size,shape, density and hardness of the abrasive material used on the extentof impregnation of the dopant in the surface using these mixed media.

One of ordinary skill in the art can appreciate the effect of the fluidstream itself, the blasting equipment using a gas medium (typically air)the effects of using inert gases as a carrier fluid e.g. N2 or noblegases such as Ar and He on the extent of impregnation of the dopant inthe surface using these mixed media.

In the case of wet blasting equipment using a liquid as a carrier fluid(normally water), One of ordinary skill in the art can appreciate theeffect of acidity and basicity on the extent of impregnation of thedopant in the surface using these mixed media.

As disclosed herein, the disclosed methods can be useful for modifyingthe surfaces of medical devices. In the context of medical deviceapplications, dopants can be active (eliciting a biological response) orpassive (not eliciting a biological response). Passive dopants can beconveyed to enhance lubricity or render a substrate radio-opaque, ofenhance wear characteristics or enhance adhesion of an ad-layer, etc.Active agents can evoke a response from the host tissue in vivo,enhancing the functionality of the device or the surgery, or deliveringa benefit as a secondary function to the device.

The process is a deposition process allowing for the addition ofmaterial(s) to a surface by a methodology typically used to removematerial from a surface. In one embodiment, the method allows for theimpregnation of the surface using:

-   -   1. abrasive bombardment to convey an additional material onto        and/or into a surface;    -   2. the removal of oxide layers from a surface in an inert        environment and the subsequent deposition of additional material        onto or into the surface prior to allowing the surface to        oxidise over again; or    -   3. a combination of 1 and 2 above

The process can be used to modify, augment or treat surfaces such as tochange surface characteristics/properties including one or more of:

-   -   morphology/topography/form/texture/roughness/microstructure    -   surface area    -   surface porosity    -   structure—order/disorder of molecular assemblies, inclusions,        vacancies, and organisation    -   crystallinity, size, distribution and orientation of crystals    -   chemistry,    -   chemical composition,        -   elemental composition        -   chemical state of elements        -   molecular composition        -   functional groups        -   molecular adlayers        -   adventitious contaminants and impurities    -   oxide layer porosity, thickness and composition,    -   biochemistry    -   biological performance    -   surface energy—lipophilic/lipophobic properties    -   wetabillity—hydrophilic and hydrophobic properties,    -   adsorption—physisorption and chemisorption    -   electric properties—surface potentials and surface charges,        dielectric constant    -   magnetic properties    -   optical properties—optical reflection/absorption    -   surface mechanical properties—Elastic/plastic nature of surface        layers, tensile/compressive forces in the surface    -   surface dynamic properties—mobility of atoms and molecules

The effect on the surface is such as to modify the chemistry andtopography of the surface material resulting in an infinite range ofmanifestations. The desired outcome resulting from the treatment isinfluenced by:

-   -   the substrate material and its surface characteristics    -   the treatment process parameters and the environmental        conditions    -   the abrasive(s) and its mechanical and chemical properties,        size, hardness, morphology etc    -   the dopant material(s) and its chemical and mechanical        properties, whether it is a carrier medium for additional agents        (e.g. therapies), or an active or passive agent, or a composite        or a cocktail mix.

In one embodiment, the methods described herein can provide one or moreof the following feature

-   -   a room temperature process        -   no degradation of the dopant material(s) due to temperature            or process        -   ability to convey temperature sensitive agents to the            surface intact.    -   one step process that is manufacturing friendly    -   no conformal polymer film required to convey therapeutic agents    -   no laminate layer results—cannot be chipped or peeled off    -   adaptable to allowing implants to be custom treated for specific        applications    -   has application in industrial sectors outside the Medical Device        sector, e.g., industries that use titanium, e.g., the aerospace        sector, the food sector (use of titanium pipes), and the        semiconductor sector, etc.

EXAMPLES Example 1

This example describes the modification of a titanium substrate usinghydroxyapatite (HA) as the dopant and alumina bead as the abrasive.

A mixed media was prepared consisting of 50 weight percent alumina(White Saftigrit: Mesh size 150, 88 micron particle size, Mohs hardness9, Guyson international Ltd) and 50 weight percent HA (Fluka Synthetichydroxyapatite (Fluka production GmbH, Buchs, Switzerland, part of theSigma-Aldrich family). A Rocatec™ grit blaster operating at a pressureof 5 bar was used to grit blast a 2 cm×2 cm CP titanium coupon (TitaniumSheet Grade 2 Medical to ASTM F67 Spec.). The nozzle to surface distancewas 1 cm and the nozzle was held at 90° to the surface. The siliconcarbide nozzle had an orifice diameter of 1 mm and traversed the surfaceat 2 cm per sec. The surface was subjected to three passes.

Two further samples of Titanium (Titanium Sheet Grade 2 Medical to ASTMF67 Spec.) were subjected to the same treatment but with the mediaconsisting of HA only.

The samples were then subjected to a cleaning treatment involving 20minutes ultrasonic washing in deionized water to remove any materialthat was not intimately affixed to the surface. After the ultrasoniccleaning the samples were rinsed with deionized water and air-dried inan oven at 95° C. for one hour.

Samples were submitted for XPS (X-Ray photoelectron spectroscopy)analysis to determine the relative concentration of Ca, P, Ti and Al atthe surfaces. FIG. 2 shows the wide scans of both samples, where (a) isan XPS survey scan of titanium treated with hydroxyapatite, and (b) isan XPS survey scan of titanium treated with the mixed media of 50:50HA/alumina. As can be seen the concentration of Ca and P (indicative ofHA) in the sample grit blasted using the mixed media technique wassignificantly higher than those seen in the sample grit blasted with HAonly. This is further confirmed by the higher resolution scans of thenarrow regions. FIGS. 3 and 4 show the Ca 2p, P 2p and Ti 2p core levelson the 50% HA: 50% Alumina and 100% HA samples. Specifically, FIGS. 3Aand 3B show comparative XPS spectra of Ca 2p (FIG. 3A) and P 2p (FIG.3B) core levels of HA only blasted cp titanium (fine line) and 50:50HA:alumina blasted cp titanium (coarse line), and FIG. 4 shows XPSspectra of the Ti 2p core level on the sample grit blasted with 100% HA(top) and the sample grit blasted with a 50:50 HA:alumina mix (bottom),indicating that the titanium is substantially covered by HA. In the caseof the mixed media grit blasted sample a significant increase in theconcentration of both Calcium and Phosphorous was observed in comparisonwith the sample blasted with HA only. Furthermore the Ca:P ratio wasfound to be 1.65 confirming that the material on the surface was indeedHA.

A further indication of the presence of a significant surface layer ofHA was the greatly reduced Ti concentration observed at the mixed mediablasted surface in comparison with that observed at the 100% HA blastedsurface indicating a layer of HA of substantial thickness (>10 nm). XPScan be used to calculate the relative concentrations of species at asurface to within an error of 10%) by normalizing the areas under thecore level curves with the RSF (Relative Scattering Factor) for eachelement. The calculated atomic ratio of Ca/Ti at the surface is given intable 1. This value best represents the level of coverage at thesurfaces. In the case of the Alumina/HA grit blasted sample the relativeconcentration of Ca to Ti is approximately 30 times that observed on the100% HA blasted sample.

TABLE 1 The atomic ratio of Ca/Ti as determined from the narrow XPSscans at the surface of the grit blasted Cp Ti surfaces BLASTING MEDIA(WEIGHT %/WEIGHT %) CA/TI RATIO RELATIVE RATIO 100% HA 0.45 0.98 100% HA0.47 1.02 50% HA:50% Alumina 13.43 29.20 50% HA:50% Silica bead 1.964.26 50% HA:50% Silica bead 2.01 4.37

In order to assess the uniformity of the HA concentration coating on thesurface XPS surface maps (0.2×0.2 mm) were run on both samples sittingon the Ti 2P and Ca 2P peaks, the right and left panels of FIG. 5respectively. The uniformity of color observed is indicative of theuniformity of distribution of the HA on the substrate material.

These results indicate that simultaneous bombardment allows the HA tobecome impregnated in the titanium surface. Further more given that bothsamples were subjected to a rigorous ultrasonic cleaning cycle, it islikely that the HA that remains on the surface was strongly bound on thesubstrate.

Example 2

This Example describes the modification of a titanium substrate usinghydroxyapatite as the dopant and silica bead as the abrasive.

A mixed media was prepared consisting of 50 weight percent silica bead(Honite 14: 75-150 micron particle size range, Mohs hardness 5 Guysoninternational Ltd) and 50 weight percent HA (Fluka Synthetichydroxyapatite). A Rocatec™ grit blaster operating at a pressure of 5bar was used to grit blast two 2 cm×2 cm CP Titanium coupon (TitaniumSheet Grade 2 Medical to ASTM F67 Spec). The nozzle to surface distancewas 1 cm and the nozzle was held at 90° to the surface. The siliconcarbide nozzle had an orifice diameter of 1 mm and traversed the surfaceat 2 cm sec⁻¹. The surface was subjected to three passes.

The samples were then subjected to a cleaning treatment involving 20minutes ultrasonic washing in deionized water to remove any materialthat was not intimately affixed to the surface. After the ultrasoniccleaning the samples were rinsed with deionized water and air-dried inan oven at 95° C. for one hour.

Samples were submitted for XPS (X-Ray photoelectron spectroscopy)analysis to determine the relative concentration of Ca, P, Ti and Si atthe surfaces. A comparison of are Ca 2p core level in one of the samplesand the 100% HA grit blasted sample is shown in the right panel of FIG.6. The P 2p core levels on both samples are shown in the left panel ofFIG. 6. In the case of the mixed media grit blasted sample a significantincrease in the concentration of both calcium and phosphorous wasobserved in comparison with the sample blasted with HA only although notas high as was the case with alumina.

The calculated atomic ratio of Ca/Ti at the surfaces is given inTable 1. In the case of the silica bead/HA grit blasted sample therelative concentration of Ca to Ti is approximately 4 times thatobserved on the 100% HA blasted samples. Table 1 also demonstrates thereproducibility of the results achievable with this technique given thatthe Ca/Ti ratio measured on the samples treated with the same mixedmedia are approximately the same. This is further demonstrated in FIG. 7which shows the similarity in the survey scans of the two samples.

Example 3

This Example describes the modification of a titanium substrate usinghydroxyapatite/gentamycin as the dopant and alumina bead as theabrasive.

A mixed media was prepared consisting of 50 weight percent alumina(White Saftigrit: Mesh size 150, 88 micron particle size, Mohs hardness9, Guyson international Ltd), 40 weight percent HA (Fluka Synthetichydroxyapatite) and 10 weight percent Gentamycin. A Rocatec™ gritblaster operating at a pressure of 5 bar was used to grit blast three0.5 cm×0.5 cm CP titanium coupons (Titanium Sheet Grade 2 Medical toASTM F67 Spec). Control coupons were blasted with HA and alumina only.The nozzle to surface distance was 1 cm and the nozzle was held at 90°to the surface. The silicon carbide nozzle had an orifice diameter of 1mm and traversed the surface at 2 cm sec⁻¹. The surface was subjected tothree passes.

The samples were then subjected to a cleaning treatment involving 20minutes ultrasonic washing in deionized water to remove any materialthat was not intimately affixed to the surface. After the ultrasoniccleaning the samples were rinsed with deionized water and air-dried inan oven at 40° C. for one hour.

The release and antibacterial activity of the antibiotic loaded surfaceswas evaluated against three bacterial species [Staphylococcus aureus(FIG. 8.1), Escherichia coli (FIG. 8.2) and Pseudomonas aeruginosa (FIG.8.3)], identified as opportunistic pathogens colonizing peri-prosthetictissue post operation and a major cause of the corrosion of implants,using an agar disc-diffusion method.

In brief, the bacteria were grown from stock cultures on brain heartinfusion (BHI) agar at 37.0 for 16 h and isolated colonies were used toseed fresh cultures in 10 ml Luria Broth (LB). After incubation at 37.0for 12-16 h with shaking (200 rpm), the cultures were diluted in MuellerHinton (MH) broth to give an OD 600 of 0.05. A 350-μl volume of eachbacterial suspension was streaked using clinical swabs on MH agar platescontaining agar to a depth of 4 mm. Following this the coupons ofmaterial were placed on the agar. The plates were inverted and incubatedunder aerobic conditions (36 h, 37° C.).

The possibility that the implant material was inhibitory with respect tomicrobial growth independent of the activity of the released Gentamycinwas eliminated by using the control samples not having the antibioticloaded on the surface (negative control) labeled 1 in FIGS. 8.1, 8.2,and 8.3 respectively. The antibiotic loaded samples are labeled 2 inFIGS. 8.1, 8.2, and 8.3 respectively.

The results are shown in FIG. 8. In the case of each of the threebacterial species tested, an inhibition zone where bacterial growth isinhibited (labeled IZ in FIGS. 8.1, 8.2 and 8.3 respectively) was seenaround the HA/Gentamycin treated samples. This indicates that theGentamycin was incorporated into the surface by the process andfurthermore that the antibiotic remains active through the blastingprocess.

Example 4

This Example describes the modification of a titanium substrate usinghydroxyapatite/vancomycin as the dopant and alumina bead as theabrasive.

A mixed media was prepared consisting of 67 weight percent alumina(White Saftigrit: Mesh size 150, 88 micron particle size, Mohs hardness9, Guyson international Ltd), 30 weight percent HA (Fluka Synthetichydroxyapatite) and 3 weight percent Vancomycin. A Rocatec™ grit blasteroperating at a pressure of 5 bar was used to grit blast eighteen 10 mmdiameter Grade 5 titanium discs (Titanium 6AL-4V Sheet Medical to ASTMF136 Spec). Control discs were blasted with HA and alumina only. Thenozzle to surface distance was 0.5 cm and the nozzle was held at 90° tothe surface. The silicon carbide nozzle had an orifice diameter of 1 mmand traversed the surface at 2 cm sec-1. The surface was subjected tothree passes.

A number of the samples were then subjected to a cleaning treatmentinvolving 20 minutes ultrasonic washing in deionized water to remove anymaterial that was not intimately affixed to the surface. After theultrasonic cleaning the samples were rinsed with deionized water andallowed to air-dry in an oven at 40° C. for one hour.

The release and antibacterial activity of the antibiotic loaded surfaceswas evaluated against the bacterial species Staphylococcus aureus (NCIMB9518), identified as an opportunistic pathogen colonizingperi-prosthetic tissue post operation, using an agar disc-diffusionmethod. FIG. 10, Plate 1 is a photograph of the inhibition zone (IZ) onan agar plate inoculated with S. aureus and exposed to thevancomycin-doped coupon.

Tests were carried out according to BSAC (British Society forAntimicrobial Chemotherapy) Disc Diffusion method for AntimicrobialSusceptibility testing (Version 2.1.1, January 2002). A bacterialsuspension containing 10⁷ CFU/ml of Staphylococcus aureus NCIMB 9518 wasprepared from fresh overnight cultures, and 0.5 ml of this suspensionwas homogeneously spread onto isosensitest agar plates. Following thisthe coupons of material were placed on the agar. The plates wereincubated under aerobic conditions (20 hours@37° C.).

The possibility that the implant material was inhibitory with respect tomicrobial growth was eliminated by using control samples not having theantibiotic loaded on the surface (negative control).

The results are shown in FIG. 10 plate 1, as demonstrated by aninhibition zone pointing to inhibited bacterial growth around theHA/vancomycin treated samples. This indicates that the vancomycin wasincorporated into the surface by the process and furthermore that theantibiotic remains active through the blasting process.

Example 5

This Example describes the modification of a titanium substrate usinghydroxyapatite/tobramycin as the dopant and alumina bead as theabrasive.

A mixed media was prepared consisting of 67 weight percent alumina(White Saftigrit: Mesh size 150, 88 micron particle size, Mohs hardness9, Guyson international Ltd), 30 weight percent HA (Fluka Synthetichydroxyapatite) and 3 weight percent Tobramycin. A Rocatec™ grit blasteroperating at a pressure of 5 bar was used to grit blast eighteen 10 mmdiameter Grade 5 titanium discs (Titanium 6AL-4V Sheet Medical to ASTMF136 Spec). Control discs were blasted with HA and alumina only. Thenozzle to surface distance was 0.5 cm and the nozzle was held at 90° tothe surface. The silicon carbide nozzle had an orifice diameter of 1 mmand traversed the surface at 2 cm sec-1. The surface was subjected tothree passes.

A number of the samples were then subjected to a cleaning treatmentinvolving 20 minutes ultrasonic washing in deionized water to remove anymaterial that was not intimately affixed to the surface. After theultrasonic cleaning the samples were rinsed with deionized water andallowed to air-dry in an oven at 40° C. for one hour.

The release and antibacterial activity of the antibiotic loaded surfaceswas evaluated against the bacterial species Escherichia coli (NCIMB12210), identified as an opportunistic pathogen colonizingperi-prosthetic tissue post operation, using an agar disc-diffusionmethod. FIG. 10, Plates 2 and 3 are photographs of the inhibition zone(IZ) on an agar plate inoculated with E. Coli and exposed to thetobramycin doped coupon.

Tests were carried out according to BSAC (British Society forAntimicrobial Chemotherapy) Disc Diffusion method for AntimicrobialSusceptibility testing (Version 2.1.1, January 2002). A bacterialsuspension containing 10⁷ CFU/ml of E. coli NCIMB 12210 was preparedfrom fresh overnight cultures, and 0.5 ml of this suspension washomogeneously spread onto isosensitest agar plates. Following this thecoupons of material were placed on the agar. The plates were incubatedunder aerobic conditions (20 hours @ 37° C.).

The possibility that the implant material was inhibitory with respect tomicrobial growth was eliminated by using control samples not having theantibiotic loaded on the surface (negative control).

The results are shown in FIG. 10, Plates 2 and 3, as demonstrated by aninhibition zone pointing to inhibited bacterial growth around theHA/Tobramycin treated samples. This indicates that the Tobramycin wasincorporated into the surface by the process and furthermore that theantibiotic remains active through the blasting process.

Example 6

This example describes the modification of a titanium substrate usinghydroxyapatite as the dopant and abrasives of varying size/hardness.

A mixed media was prepared consisting of 80 weight percent abrasive (50,100 micron particle size Silica bead, Mohs hardness 6, Comco Inc.; 50,100, 150 micron particle size Alumina bead, Mohs hardness 9, Comco Inc.)and 20 weight percent HA (Fluka Synthetic hydroxyapatite). A ComcoMB1000 Micro-blaster operating at a blast pressure of 80 psi was used togrit blast nine 10 mm diameter Grade 5 titanium discs (Titanium 6AL-4VSheet Medical to ASTM F136 Spec) for each abrasive type. The nozzle tosurface distance was 15 mm and the nozzle was held at 90° to thesurface. The HP (high performance) nozzle used had an orifice diameterof 0.060 inch and traversed the surface at 3.175 mmsec-1. The surfacewas subjected to one pass through the centre of each metal disc.

The samples were then subjected to a cleaning treatment involving 20minutes ultrasonic washing in deionized water to remove any materialthat was not intimately affixed to the surface. After the ultrasoniccleaning the samples were rinsed with deionized water and air-dried inan oven at 40° C. for one hour.

Samples were submitted for XPS (X-Ray photoelectron spectroscopy); FTIR(Fourier Transform Infrared Spectroscopy); Surface Roughnessanalysis—Stylus Profilometry; (XRD) X-Ray Diffraction, to determine therelative concentration of Ca, P, and Ti at the surface of each sample inconjunction with the morphological characteristics of each sample.

Table 2 indicates the results shown for titanium blasted with abrasivesof varying particle size and hardness, as indicated by XPS. FIGS. 11Aand 11B show FTIR spectra plots for duplicate 100 μm and 150 μm aluminabead respectively.

TABLE 2 XPS atomic concentrations of surface elements (and Ca:P ratio)as a function of blast particle size and hardness 150 μM Alu 100 μM 50μM Alu 100 μM Alu Oxide Elements Control Glass Bead Oxide Bead OxideBead Bead O 1s 37.78 54.80 53.38 54.71 54.12 C 1s* 44.33 20.73 24.9523.08 24.02 N 1s 3.37 0.25 0.57 0.84 0.55 Ti 2p 5.00 0.23 1.18 1.32 0.86Ca 2p 0.28** 14.58 12.23 12.36 11.99 P 2p 0.29** 9.40 7.69 7.68 8.47 Al2p 8.94*** — — — — Ca/P Ratio n/a 1.55 1.61 1.61 1.42 *Normaladventitious Carbon level on Titanium & its alloys - can be higherdepending on the forming/manufacturing processes undergone.**Adventitious HA due to cross contamination from treated samples.***Aluminium in the TiAl₄V₆ alloy (Grade 5 Titanium).

FIG. 11A shows FTIR spectra of duplicate 100 μm alumina bead samples (a)and (b), and FIG. 11B shows FTIR spectra of 150 duplicate μm aluminabead samples (a) and (b).

Table 3 indicates the results shown for abrasives of varying particlesize and hardness, as indicated by stylus profilometry.

TABLE 3 Stylus profilometry of surface topography showing roughness as afunction of blast particle size and hardness 100 μM 50 μM Alu 100 μM Alu150 μM Alu Glass Bead Oxide Bead Oxide Bead Oxide Bead Avg. Surface 0.350.37 0.62 0.61 Roughness (μM) Std Dev 0.06 0.03 0.05 0.02

FIGS. 12A and 12B show XRD patterns for 50 μm and 100 μm alumina beadsamples, respectively.

The data indicates that varying the size and hardness of the abradingmedia will result in varying surface morphology as expected, but also indifferences in the quantity and coverage of Hydroxyapatite in theadlayer.

Example 7

This Example describes the modification of a titanium substrate bydelivering hydroxyapatite as the dopant in one particle stream andalumina bead as the abrasive in a separate particle stream using a twinnozzle, while varying blast parameters and the abrasive to dopant ratio.

An experiment was conducted to control the uniformity of the flow ofabrasive and dopant materials to the surface being treated by loadingthe materials into the reservoirs of two separate Comco MB 1000Micro-blaster units feeding separate nozzles aimed at the same point onthe surface, as schematically depicted in FIG. 9C. The followingparameters were varied; nozzle diameters, distance of nozzles from thesurface, blast pressure, incident angle and the ratio of abrasive todopant at the point of contact with the substrate (See Table 4: TestParameters variations to study effect on HA deposition and surfacetopography). 100 micron particle size Alumina bead, (Mohs hardness 9,Comco Inc.) was used in all test runs. The Synthetic HA (Glantreo Ltd,Cork, Ireland) used had a particle size range of 20 to 60 microns. Nine10 mm diameter Grade 5 titanium discs (Titanium 6AL-4V Sheet Medical toASTM F136 Spec) were treated for each run. The surface was subjected toone pass through the centre of each metal disc at a feed rate of 3.175mmsec-1.

TABLE 4 Test Parameter variations to study effect on HA deposition andsurface topography E: Abrasive A: Nozzle B: Nozzle C: Blast D: Incidentto Dopant Run Diameter Distance Pressure Angle Ratio 1 30 12 95 90 70:302 30 18 95 45 90:10 3 60 18 60 90 90:10 4 30 18 95 90 90:10 5 46 15 8067.5 80:20 6 30 12 95 45 70:30 7 60 12 60 90 70:30 8 30 12 60 45 90:10 930 18 60 90 70:30 10 60 18 95 45 70:30 11 60 12 60 45 70:30 12 60 18 6045 90:10 13 30 12 60 90 90:10 14 60 12 95 90 90:10 15 60 12 95 45 90:1016 30 18 60 45 70:30 17 60 18 95 90 70:30

The samples were then subjected to a cleaning treatment involving 20minutes ultrasonic washing in deionized water to remove any materialthat was not intimately affixed to the surface. After the ultrasoniccleaning the samples were rinsed with deionized water and air-dried inan oven at 40° C. for one hour.

Samples were submitted for XPS (X-Ray photoelectron spectroscopy); FTIR(Fourier Transform Infrared Spectroscopy); Surface Roughnessanalysis—Stylus Profilometry; to determine the relative concentration ofCa, P, and Ti at the surface of each sample in conjunction with themorphological characteristics of each sample. Results for XPS analysisare shown in Table 5 and results for stylus profilometry are shown inTable 6.

TABLE 5 XPS atomic concentrations of surface elements (and CA:P ratio)as a function of varying blast parameters and abrasive to dopant ratio.Element 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 O 1s 45.7 48.7 49.343.9 44.8 44.6 51.1 39.8 48.0 42.9 51.0 50.0 50.8 46.2 48.8 47.8 53.2 C1s * 32.6 32.9 32.6 36.2 34.2 42.7 30.1 44.7 30.4 40.3 36.5 34.2 27.137.3 31.3 31.0 30.1 Na 1s 0.6 0.3 0.0 0.4 0.3 1.1 1.9 0.7 0.2 0.7 1.91.8 0.4 3.6 1.3 0.4 2.1 Ti 2p 0.4 2.9 2.0 2.0 1.8 5.7 3.7 6.7 0.2 3.36.0 5.2 0.7 2.8 3.7 0.7 4.7 Ca 2p 13.3 10.1 10.3 11.2 12.3 4.0 8.2 5.613.5 7.9 3.1 5.7 13.9 6.8 9.3 12.9 6.4 P 2p 7.4 5.0 5.8 6.2 6.5 1.9 4.42.6 7.8 4.9 1.4 3.1 7.1 3.3 5.5 7.2 3.5 Ca/P 1.81 2.00 1.77 1.80 1.892.01 1.99 2.17 1.73 1.61 2.3 1.83 1.94 2.04 1.72 1.80 1.84 Ratio *Normal adventitious Carbon level on Titanium & its alloys - can behigher depending on the forming/manufacturing processes undergone.

TABLE 6 XPS atomic concentrations of duplicate HA controls Atomic HApowder control Concentration (%) Peak Position BE (eV) Point A Point B O1s 532.5 38.02 40.29 Ca 2p 346.5 13.08 13.72 C 1s 285 41.58 38.65 P 2p133.5 7.31 7.34 Ca:P ratio 1.79 1.87

TABLE 7 Stylus profilometry of surface roughness as a function ofvarying blast parameters and abrasive to dopant ratio 1 2 3 4 5 6 7 8 910 11 12 13 14 15 16 17 Average 0.50 0.46 0.59 0.40 0.55 0.41 0.51 0.460.43 0.57 0.53 0.55 0.51 0.53 0.55 0.48 0.54 Surface Roughness (μM) StdDev 0.02 0.03 0.05 0.03 0.02 0.03 0.03 0.02 0.03 0.04 0.01 0.04 0.030.02 0.05 0.04 0.04

The data indicates that varying the blasting parameters andabrasive:dopant ratio, as outlined in the experiment, results in varyingsurface morphology as expected, but also in differences in the quantityand coverage of hydroxyapatite in the adlayer. The HA controls dataindicates that the process does not have a detrimental effect on the HAquality as exemplified by the Ca:P (calcium to phosphate) ratio data, asshown in FIG. 13, XPS Survey Spectra for duplicate HA controls.

Example 8

This Example describes the modification of a stainless steel substrateand a Grade 2 titanium substrate using hydroxyapatite as the dopant andalumina bead as the abrasive.

A mixed media was prepared consisting of 80 weight percent alumina(White Saftigrit: Mesh size 150, 88 micron particle size, Mohs hardness9, Guyson international Ltd) and 20 weight percent HA (Synthetic HA,particle size 20-60 microns, Glantreo Ltd, Cork, Ireland). A Rocatec™grit blaster operating at a pressure of 5 bar was used to grit blast aStainless Steel tube (Medical grade Stainless Steel to ASTM 1586 spec)used to manufacture cardiac stents) and Grade 2 Titanium sheet (TitaniumSheet Grade 2 Medical to ASTM F67 Spec). The nozzle to surface distancewas 0.5 cm and the nozzle was held at 90° to the surface. The siliconcarbide nozzle had an orifice diameter of 1 mm and traversed the surfaceat 2 cm sec-1. The surface was subjected to three passes.

The sample was then subjected to a cleaning treatment involving 20minutes ultrasonic washing in deionized water to remove any materialthat was not intimately affixed to the surface. After the ultrasoniccleaning the samples were rinsed with deionized water and air-dried inan oven at 40° C. for one hour.

Samples were submitted for SEM/EDX (Scanning Electron Microscopy/EnergyDispersive X-Ray) analysis and AFM analysis to determine if HA wasaffixed to the surface of both materials. FIGS. 14 (SEM) and 15 (EDX)show a well affixed layer of HA on the surface of the stainless steelsample that gives good coverage as indicated in Table 8, with athickness up to 6.5 microns (see FIG. 14). As expected the CP Titaniumdisplayed an adherent layer of HA, see FIG. 16 (SEM) and FIG. 17 (EDX),while Table 9 shows the elemental analysis of the surface. FIGS. 18A and18B (AFM) show that the affixed HA layer has a thickness of 7 microns.

TABLE 8 Elemental Analysis of the HA-Stainless Steel interface ElementWeight % Atomic % C 33.19 43.85 O 47.78 47.39 Al 2.12 1.25 Si 0.58 0.33P 6.14 3.14 Ca 10.19 4.04 Ca/P = 1.28

TABLE 9 Elemental Analysis of the HA-Titanium interface Element Weight %Atomic % O 33.76 58.38 P 6.41 5.73 Ca 11.81 8.15 Ti 48.02 27.73 Ca/P =1.42

Example 9

This Example describes the modification of a titanium substrate usingAlumina bead as the abrasive and a nano-porous silica as the dopant.Nanoporous silica is known as a suitable drug elution carrier.

A mixed media was prepared consisting of 50 volume percent alumina (100micron particle size, Mohs hardness 9, Comco Inc.) and 50 volume percentMesoporous Silica (particle size is approx. 1 microns; pore size 10nanometers, Glantreo Ltd, Cork, Ireland). A Comco MB1000 Micro-blasteroperating at a blast pressure of 80 psi was used to grit blast nine 10mm diameter Grade 5 titanium discs (Titanium 6AL-4V Sheet Medical toASTM F136 Spec). The nozzle to surface distance was 15 mm and the nozzlewas held at 90° to the surface. The HP (high performance) nozzle usedhad an orifice diameter of 0.060 inch and traversed the surface at 3.175mm sec-1. The surface was subjected to one pass through the centre ofeach metal disc.

The samples were then subjected to a cleaning treatment involving 20minutes ultrasonic washing in deionized water to remove any materialthat was not intimately affixed to the surface. After the ultrasoniccleaning the samples were rinsed with deionized water and air-dried inan oven at 40° C. for one hour.

Samples were submitted for SEM (Scanning Electron Microscopy) analysisto determine the presence of the Silica micro-particles on the surfaceof the Grade 5 Titanium. FIG. 19 displays the Silica particles affixedto the surface.

Example 10

This Example describes the modification of aluminum and nitinolsubstrates with nanoporous HA (a drug elution carrier) as a dopant andalumina bead as an abrasive.

A mixed media was prepared consisting of 90 weight percent alumina(White Saftigrit: Mesh size 150, 88 micron particle size, Mohs hardness9, Guyson international Ltd) and 10 weight percent nanoporous HA(particle size average 50 Microns; irregular non-spherical particles;pore size 3-4 nanometers, Glantreo Ltd, Cork, Ireland). A Rocatec™ gritblaster operating at a pressure of 5 bar was used to grit blast Aluminumand Nitinol. The nozzle to surface distance was 0.5 cm and the nozzlewas held at 90° to the surface. The silicon carbide nozzle had anorifice diameter of 1 mm and traversed the surface at 2 cm sec-1. Thesurfaces were subjected to three passes.

The samples were then subjected to a cleaning treatment involving 20minutes ultrasonic washing in deionized water to remove any materialthat was not intimately affixed to the surface. After the ultrasoniccleaning the samples were rinsed with deionized water and air-dried inan oven at 40° C. for one hour.

Samples were submitted for SEM (Scanning Electron Microscopy) analysisto determine the presence of the Nanoporous HA on the aluminum andnitinol surfaces. FIGS. 20A and 20B are SEM images of the nanoporous HAadlayer on the aluminum surface, and FIG. 21 is a SEM image of thenanoporous HA adlayer on the nitinol surface.

The invention claimed is:
 1. A method of treating a metal article, themethod comprising: delivering simultaneously a first set of particlescomprising a first material and a second set of particles comprising asecond material different from the first material from at least onefluid jet to a surface of the article, wherein the second set ofparticles are non-spherical; and removing a metal oxide from the surfacewith the second set of particles while simultaneously impregnating thesurface with the first set of particles.
 2. The method of claim 1,wherein impregnating the surface with the first set of particlesmodifies a surface energy of the surface.
 3. The method of claim 1,wherein impregnating the surface with the first set of particlesmodifies a wettability of the surface.
 4. The method of claim 1, furthercomprising adhering a third material to the surface after impregnatingthe surface with the first set of particles.
 5. The method of claim 1,wherein the first and second sets of particles are delivered to thesurface at a same incident angle.
 6. The method of claim 1, wherein theat least one fluid jet forms an angle with the surface ranging from 30degrees to 90 degrees.
 7. The method of claim 1, wherein the at leastone fluid jet forms an angle with the surface ranging from 70 degrees to90 degrees.
 8. The method of claim 1, wherein the first and second setsof particles are delivered to the surface by a single fluid jet.
 9. Themethod of claim 1, wherein the metal article comprises a pure metal, ametal alloy, or an intermetal.
 10. The method of claim 1, wherein themetal article comprises a metal or metal alloy comprising titanium,iron, carbon, cobalt, aluminum, nickel, tantalum, niobium, chromium,tantalum, or a precious metal.
 11. The method of claim 10, wherein themetal article comprises a metal alloy comprising carbon steel, stainlesssteel, cobalt chrome, or nitinol.
 12. The method of claim 1, wherein thefirst material comprises a polymer, a phosphate compound, carbon, or acombination thereof.
 13. The method of claim 1, wherein the second setof particles have a particle size of about 100 μm.
 14. The method ofclaim 1, wherein the at least one fluid jet operates at a pressureranging from 0.5 bar to 100 bar.
 15. A method of treating a metalarticle, the method comprising: delivering simultaneously a first set ofparticles comprising a first material and a second set of particlescomprising a second material different from the first material from atleast one fluid jet to a surface of the article, wherein the second setof particles are non-spherical; and removing a metal oxide from thesurface with the second set of particles while simultaneouslyimpregnating the surface with the first set of particles; whereinimpregnating the surface with the first set of particles modifies asurface energy and a microstructure of the surface.
 16. The method ofclaim 15, further comprising adhering a third material to the surfaceafter impregnating the surface with the first set of particles.
 17. Themethod of claim 15, wherein the first material comprises a polymer, aphosphate compound, carbon, or a combination thereof.
 18. The method ofclaim 15, wherein the delivering, the removing, and the impregnating areperformed under an inert atmosphere.
 19. A method of treating a metalarticle, the method comprising: delivering simultaneously a first set ofparticles comprising a first material and a second set of particlescomprising a second material different from the first material from atleast one fluid jet to a surface of the article, wherein the second setof particles are non-spherical; removing a metal oxide from the surfacewith the second set of particles while simultaneously impregnating thesurface with the first set of particles, wherein impregnating thesurface with the first set of particles modifies a surface energy of thesurface; and adhering a third material to the surface after impregnatingthe surface with the first set of particles.
 20. The method of claim 19,wherein at least one of the first material or the third materialcomprises a polymer.